We are studying the reactions of osmium tetroxide-ligand systems with thymine and uracil derivatives for three principal biochemical applications. The first of these is to synthesize reagents useful in the preparation of heavy-atom isomorphous derivatives of t-RNA for x-ray crystallographic analysis. The second is to develop reagents useful for the determination of the base sequence in polynucleotides by direct electron microscopic visualization of single heavy atoms. The third objective in the nucleic acid field is alteration of the specificity of deoxyribonucleases by specific modifications of the DNA substrate using osmium reagents. Our most general objective is a systematic study of the reactions of osmium tetroxide and its reduction products with other tissue components so as to provide electron microscopists, histologists, and pathologists with a firm chemical basis for the interpretation of their observations on fixed specimens.